Tricyclic lactams and derivatives useful in increasing cardiac contractility

ABSTRACT

Disclosed are 5,6-dihydro benzo[f]quinolines and derivatives which are effective in increasing cardiac contractility. These compounds are useful in the treatment of congestive heart failure.

SUMMARY OF THE INVENTION

This invention relates to certain tricyclic lactams which are useful in increasing cardiac contractility, to pharmaceutical compositions containing such compounds and to a method of treating a patient by administering an effective amount of such compounds to increase cardiac contractility in said patient.

The compounds of the present invention are represented by the formula ##STR1## wherein R is hydrogen or lower alkyl; R¹ is hydrogen, hydroxy, lower alkoxy, cyano,

lower alkyl, halogen, --NR² R³, --CONR² R³,

--NHCOR², --COOR² (wherein R² and R³ are

independently hydrogen, lower alkyl or hydroxy

lower alkyl) or ##STR2## wherein M is sulfur or NH; with the proviso that R and R¹ are not both hydrogen;

Z is selected from the group consisting of ##STR3## wherein n is 1,2,3 or 4; A is a substituted or unsubstituted benzo or pyrido ring which when substituted have 1 to 3 substituents independently selected from halogen, hydroxy, lower alkyl and lower alkoxy;

and pharmaceutically acceptable salts thereof.

Unless otherwise stated, the term "lower alkyl" includes branched- and straight-chain alkyl groups of from 1 to 6 carbon and includes, for instance, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl and the like.

The term "lower alkoxy" includes both branched and straight-chain alkoxy groups of 1 to 6 carbons and includes for instance, methoxy, ethoxy, isopropoxy, t-butoxy, n-hexoxy and the like.

The term "halo" or "halogen" means chloro and bromo.

The term "phamaceutically acceptable salts" includes the pharmaceutically acceptable acid addition salts of the compounds of formula I derived from a variety of organic and inorganic acids, such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic, oleic, succinic, tartaric, cinnamic, acetic, benzoic, ascorbic and other organic and inorganic acids which form pharmaceutically acceptable addition salts.

The nomenclature employed throughout this specification has been assigned from Parent Compound Handbook (American Chemical Society).

The term A is a "pyrido ring" means the following rings: ##STR4## each substituted or unsubstituted as described above and with conventional numbering employed therewith.

Preferred R lower alkyl groups are methyl, ethyl, n-propyl and isopropyl. Most preferably R is hydrogen or methyl.

Preferred R¹ groups are hydroxy, lower alkoxy, cyano, --NR² R³, --CONR² R³, --NHCOR², wherein R² and R³ are independently hydrogen, lower alkyl or hydroxy lower alkyl.

More preferred R¹ groups are cyano, amino and ##STR5##

Preferably A is a substituted or unsubstituted benzo ring or a 3-pyrido ring.

Preferred loweralkyl substituents on the pyrido and benzo rings are methyl, ethyl, isopropyl, and n-propyl.

Preferred pyrido and benzo lower alkoxy substituents are methoxy, ethoxy, isopropoxy, and n-propoxy.

Particularly preferred are pyrido and benzo substituted with 1 to 3 substituents independently selected from chloro, bromo, amino, methoxy, methyl and hydroxy.

Of the above preferred compounds, those wherein Z is methylene, ethano and etheno are particularly preferred.

Most preferably Z is either ethano or etheno.

Preferred compounds of this invention include 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one and 2-cyano-benzo[f]quinolin-3(4H)-one.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention have been found to increase cardiac contractility. As such, the compounds of this invention are useful in the treatment of congestive heart failure.

The compounds were tested for their ability to increase cardiac contractility both in vitro and in vivo.

In vitro tests were conducted on left atria obtained from guinea pigs employing the method described in J. Pharmacol. Exp. Ther. 217, 708-713 (1981). Increases in cardiac contractility were found at concentrations ranging from 1 μgm/ml to 32 μgm/ml

In vivo tests were conducted on open-chest barbituated-anesthetized dogs employing the method described in J. Pharmacology Exp. Ther. 218, 444-452 (1981). Increases in cardiac contractility were generally found at dosage levels of 0.1 mg/kg to 3.2 mg/kg.

The present invention contemplates a method for increasing cardiac contractility in a patient requiring such treatment which comprises administering parenterally an amount effective in increasing cardiac contractility of a compound of Formula I.

The compounds are administered in a variety of formulations. Preferably the compounds are administered parenterally. The compounds may be combined with any suitable pharmaceutical carrier and administered in a variety of formulations. The compounds may also be administered transdermally.

Typically, a daily dosage regimen would generally be 0.1 to 10 gm/day parenterally. Preferably, the compounds of this invention should be administered as a constant infusion titrated to the desired clinical effect. The actual dose to be administered is determined by the clinician and is dependent upon various factors such as the particular compound employed, age and weight of the subject, the severity of the disease, and the individual's response. The daily dosage may be administered either singly or divided proportionally into several dosages.

The methods of this invention are implemented using pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an amount effective in increasing cardiac contractility of a compound of Formula I.

In treating certain patients with the compounds of this invention, it is possible to include other pharmaceutically active ingredients in the same dosage unit.

The compounds of this invention may be readily prepared in a two-step synthesis as shown in reactions (1) and (2) below: ##STR6## wherein R and A are as defined above, n is 1, 2, 3, or 4 and R⁸ is cyano, lower alkoxy or lower alkyl.

Reaction (1) is the condensation of an amide acetal with the active ketone, II, to give IV. For example, the reaction can be conducted by adding an essentially equimolar amount of N,N-dimethylformamide dimethyl acetal, to II. The reaction is generally conducted neat (i.e., without solvent). Reaction pressure is not critical and for convenience the reaction is generally conducted at atmospheric pressure. The reaction is generally conducted at reflux and is generally complete from within 1/2 to 4 hours. The product, IV, may then be isolated and purified by conventional procedures such as extraction, filtration, chromatography, distillation, or alternatively, may be used in succeeding reactions without purification.

The cyclization of reaction (2) may be accomplished by addition of 1 to 1.5 equivalents of the substituted acetamide, V, to IV. The reaction is conducted in the liquid phase employing an inert organic solvent such as dimethylformamide. An excess (3 equivalents) of a base such as sodium methoxide, sodium ethoxide and the like is employed in the system. Reactiion pressure is not critical and for convenience the reaction is generally conducted at atmospheric pressure. The reaction is generally conducted at from 60° C. to 100° C. and is generally complete from within 2 to 10 hours. The product, VI, may then be isolated and purified by conventional procedures such as extraction, filtration, chromatography, distillation, or alternatively, may be used in succeeding reactions without isolation and/or purification.

Compounds of formula I wherein Z is etheno (i.e., --CH═CH--) may be preferably prepared by oxidation of the corresponding ethano (--CH₂ CH₂ --) compounds.

The 2-cyanopyridin-3-(4H)-ones, VI, are readily derivatized by procedures recognized in the art as shown in the following flow diagram, wherein X'₂ is either Cl₂ or Br₂. ##STR7##

In the following discussion, partial structures (i.e. formulae A-J, VII-IX) are named relative to the pyridine structure shown, rather than relative to the tricyclic lactam structure, since the numbering of the tricyclic lactam systems changes for different A-rings and different Z groups.

The 3-cyanopyridin-2(1H)-one, A, is readily converted to the carboxamide, B, by treatment with concentrated acid such as concentrated sulfuric acid. The carboxamide may then be converted to the amine, C, by treatment with bromine and base. The amine may then be acylated by reaction with an acid halide to form D.

The 3-cyanopyridin-2(1H)-one A may also be hydrolyzed to the carboxylic acid, E, by treatment with aqueous acid such as aqueous sulfuric acid. The carboxylic acid may then be readily esterified under acidic or basic conditions to form the ester, F.

The ester may be converted to the amide, G, by treatment with an excess of ammonia or the appropriate amine in an inert hydroxylic solvent, water, or a mixture of water and an inert hydroxylic solvent.

The 3-carboxylic acid may be readily decarboxylated by heating to produce H which may then be treated with chlorine or bromine to produce the 3-halopyridin-2(1H)-one, L.

The 3-halopyridin-2(1H)-one, L, may be treated with ammonia or a mono or diloweralkylamine to produce the 3-amino or 3-mono or diloweralkylamino product.

The conversion of the 3-halogen to the 3-hydroxypyridin-3(4H)-one, K, is described in U.S. Pat. No. 4,225,601, column 24, which is incorporated herein by reference.

The 3-cyanopyridin-2(1H)-ones, VII, may be converted to the thiocarboxamide group as shown in reaction (3) below: ##STR8## wherein R is as defined above.

The reaction is known in the art and is described by J. Chem. Soc., 742-744 (1952). The reaction is accomplished by treating the 3-cyanopyridin-2(1H)-one, VII, with hydrogen sulfide and triethylamine in pyridine at or above room temperature. The product, VIII, is then isolated and purified by conventional procedures such as extraction, distillation, chromatography, filtration and the like.

The 3-cyanopyridin-2(1H)-ones, VII, may also be converted to the carboxamidine group by treatment with liquid ammonia and ammonium chloride at elevated temperatures (80° C.) as shown in reaction (4) below: ##STR9##

The starting materials for reaction (1), the 2-tetralone, substituted 2-tetralones, 2-indanone, benzocycloheptan-2-one, benzocyclooctan-2-one and N,N-dimethylformamide dimethyl acetal are known in the art.

A general method for the synthesis of the 5,6,7, 8-tetrahydroquinolin-7 (or 6)-one; 5,7-dihydrocyclopenta[c]pyridin-6-one; and 5,6,7,8,9,10-hexahydrocycloocta[1,2-b]pyridin-3(4H)-one starting materials for reaction (1), is reported by Maeda and Ohsugi, Chem. Pharm. Bull., 16, 897-908 (1968).

The following non-limiting examples describe in detail the preparation of the compounds and compositions of the present invention. As used herein, the term "room temperature" refers to about 20° C. to 25° C. Unless otherwise stated, all temperature and temperature ranges are in degrees Celsius.

EXAMPLE 1 Preparation of 1-Dimethylaminomethylene-2-tetralone

Heat 8.0 ml of 2-tetralone and 12.0 ml of dimethylformamide dimethyl acetal under reflux at 80° for 11/2 hours. Concentrate the reaction mixture in vacuo. Dissolve the residue in hot methanol, add charcoal, filter, and concentrate the filtrate in vacuo to give the title compound, an amber oil.

EXAMPLE 2 Preparation of 2-Cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one

Heat 11.4 g of 1-dimethylaminomethylene-2-tetralone, 4.46 gm of cyanoacetamide and 6.6 gm of sodium methoxide in 100 ml of dimethylformamide for 8 hours at 80°. Cool and dilute the reaction mixture with 150 ml of acetonitrile. Remove the tan solid by filtration. Dissolve the solid in hot water and filter the mixture. Acidify this aqueous solution with concentrated hydrochloric acid to give a tan precipitate. Filter and wash the tan solid with chloroform to give the title compound, m.p. 301°-3°. Concentrate the remaining dimethylformamide:acetonitrile solution in vacuo to give a green-black residue and chromatograph on 800 ml of silica gel using cloroform:methanol 98:2 as eluant to give an additional amount the title compound.

EXAMPLE 2b Preparation of 2-Cyanobenzo[f]quinolin-3(4H)-one

Add 11.1 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one to 1500 ml of anhydrous 1,4-dioxane containing 33.0 gm of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone). Heat the system at reflux for 16 hours. Filter the solution and isolate the title compound.

Similarly the following compounds of this invention may be prepared by using the procedures of the above examples and employing the appropriate reagents:

3-cyano-1,9-dihydro-2H-cyclopenta[1,2-b:4,3-b']dipyridin-2-one;

3-ethyl-1,9-dihydro-2H-cyclopenta[1,2-b:4,3-b']dipyridin-2-one;

3-cyano-1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one;

1,9-dihydro-4-methyl-2H-cyclopenta[1,2-b:4,3-c']dipyridin-2-one;

3-cyano-1,9-dihydro-2H-cyclopenta[1,2-b:4,3-c']dipyridin-2-one;

3-cyano-4-methyl-1,9-dihydro-2H-cyclopenta[1,2-b:4,3-c']dipyridin-2-one;

3-ethoxy-1,9-dihydro-5,6,8-trimethyl-2H-cyclopenta[1,2-b:3,4-c']dipyridin-2-one;

3-cyano-1,9-dihydro-2H-cyclopenta[1,2-b:3,4-c']dipyridin-2-one;

3-cyano-4-ethyl-1,9-dihydro-2H-cyclopenta[1,2-b:3,4-b']dipyridin-2-one;

3-cyano-1,9-dihydro-2H-cyclopenta[1,2-b:3,4-b']dipyridin-2-one;

2-cyanobenzo[f]quinolin-3(4H)-one;

1-n-propylbenzo[f]quinolin-3(4H)-one;

2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one;

5,6,-dihydro-2,8-dimethoxybenzo[f]-quinolin-3(4H)-one;

2-cyano-5,6,-dihydro-1-methylbenzo[f]quinolin-3(4H)-one;

9-cyano-1,7-phenanthrolin-8(7H)-one;

9-cyano-4,7-phenanthrolin-8(7H)-one;

9-methoxy-2,3-dimethyl-4,7-phenanthrolin-8(7H)-one;

9-cyano-3,7-phenanthrolin-8(7H)-one;

9-cyano-1,4-dimethyl-2,7-phenanthrolin-8(7H)-one;

9-cyano-5,6-dihydro-4,7-phenanthrolin-8(7H)-one;

9-cyano-5,6-dihydro-1,7-phenanthrolin-8(7H)-one;

9-cyano-5,6,-dihydro-3,7-phenanthrolin-8(7H)-one;

9-cyano-5,6-dihydro-2,7-phenanthrolin-8(7H)-one;

5,6-dihydro-9-methoxy-1,3-dimethyl-2,7-phenanthrolin-8(7H)-one;

5,6-dihydro-10-methyl-2,7-phenanthrolin-8(7H)-one;

2-cyano-4,5,6,7-tetrahydro-3H-benzo[3,4]cyclohepta[1,2-b]pyridin-3-one;

10-cyano-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:4,3-b']pyridin-9-one;

5,6,7,8-tetrahydro-10-methoxy-1,2,3-trimethyl-9H-cyclohepta-[1,2-4,3-b']dipyridin-9-one;

10-cyano-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:4,3-c']dipyridin-9-one;

5,6,7,8-tetrahydro-10-methoxy-1,2,4-trimethyl-9H-cyclohepta-[1,2-b:4,3-c']dipyridin-9-one;

5,6,7,8-tetrahydro-10-methoxy-1,2,3-trimethyl-9H-cyclohepta-[1,2-b:3,4-b']dipyridin-9-one;

10-cyano-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:3,4-c']dipyridin-9-one;

10-cyano-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:3,4-b']dipyridin-9-one;

2-cyano-5,6,7,8-tetrahydrobenzo[3,4]cycloocta[1,2-b]pyridin-3(4H)-one; and

11-cyano-5,6,7,8-tetrahydrocycloocta[1,2-b:4,3-c']-dipyridin-10(9H)-one.

EXAMPLE 3 Preparation of 5,6-Dihydrobenzo[f]quinolin-3(4H)-one-2-carboxamide

Heat 5.5 gm 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)one in 50 ml of 90% sulfuric acid at 100° for 11/2 hours. Cool the reaction mixture, pour into ice water and basify the aqueous mixture with 50% sodium hydroxide to give a tan precipitate. Filter the mixture and recrystallize the solid (dimethylformamide:acetonitrile) to give the title compound.

EXAMPLE 4 Preparation of 5,6-Dihydrobenzo[f]quinolin-3(4H)-one-2-carboxamidine Hydrochloride

Add 2.10 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one to 0.53 gm of ammonium chloride in liquid ammonia in a steel bomb. Heat the system to 80° C. for 24 hours. Cool the system to room temperature and remove the ammonia. Isolate 5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxamidine hydrochloride.

EXAMPLE 5 Preparation of 5,6-Dihydrobenzo[f]quinolin-3(4H)-one-2-thiocarboxamide

Add 4.20 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one to 50 gm of pyridine. Add 3.0 ml of triethylamine to the system. Cool the system to 0°-5° C. and treat the system with hydrogen sulfide gas until the reaction is complete as indicated by thin layer chromatography. Isolate 5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-thiocarboxamide.

EXAMPLE 6 Preparation of 5,6-Dihydrobenzo[f]quinolin-3(4H)-one-2-carboxylic acid

Add 6.3 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one to 100 ml of 50% aqueous sulfuric acid. Heat the system to reflux for 6 hours. Cool the reaction mixture, pour into ice water and isolate the title compound.

EXAMPLE 7 Preparation of Methyl 5,6-Dihydrobenzo[f]quinolin-3(4H)-one-2-carboxylate

Add 6.0 gm of 5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxylic acid to 100 ml of methanol. Dropwise at 0° C., add 10 ml of thionyl chloride to the system. Heat the system at reflux for 6 hours. Remove the solvent by stripping. Isolate the title compound.

EXAMPLE 8 Preparation of 5,6-Dihydrobenzo[f]quinolin-3(4H)-one-2-N,N-dimethylcarboxamide

Add 2.7 gm of methyl 5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxylate to a steel bomb containing 40% aqueous dimethylamine. Heat the system in an oil bath at 100° for 16 hours. Stop the reaction and cool the system to room temperature. Extract the product with chloroform and wash the chloroform solution with water. Treat the chloroform solution with charcoal and then filter. Dry the chloroform solution with anhydrous sodium sulfate and filter. Remove the solvent by stripping to give the title compound.

Similarly, the following compounds of this invention may be prepared by using the above procedures and employing the appropriate starting materials:

benzo[f]quinolin-3(4H)-one-2-carboxylic acid;

1,9-dihydro-2H-cyclopenta[1,2-b:4,3-b']dipyridin-2-one-3-carboxylic acid;

Methyl benzo[f]quinolin-3(4H)-one-2-carboxylate;

1,9-dihydro-2H-cyclopenta[1,2-b:4,3-b']dipyridin-2-one-3-carboxamide;

1,9-dihydro-2H-indeno[2,1-b]pyridin-2-one-3-thiocarboxamide;

1,9-dihydro-2H-indeno[2,1-b]pyridine-2-one-3-carboxamide;

1,9-dihydro-2H-cyclopenta[1,2-b:4,3-c']dipyridin-2-one-3-carboxamide;

1,9-dihydro-2H-cyclopenta[1,2-b:3,4-c']dipyridin-2-one-3-carboxamidine;

1,9-dihydro-2H-cyclopenta[1,2-b:3,4-b']dipyridin-2-one-3-carboxamide;

benzo[f]quinolin-3(4H)-one-2-carboxamide;

benzo[f]quinolin-3(4H)-one-2-thiocarboxamide;

benzo[f]quinolin-3(4H)-one-2-carboxamidine;

5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxamide;

5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-thiocarboxamide;

5,6-dihydrobenzo[f]quinolin-3(4H)-one-2-carboxamidine;

1,7-phenanthrolin-8(7H)-one-9-carboxamidine;

4,7-phenanthrolin-8(7H)-one-9-thiocarboxamide;

3,7-phenanthrolin-8(7H)-one-9-carboxamide;

5,6-dihydro-4,7-phenanthrolin-8(7H)-one-9-carboxamide;

5,6-dihydro-1,7-phenanthrolin-8(7H)-one-9-carboxamidine;

5,6-dihydro-10-methyl-3,7-phenanthrolin-8(7H)-one-9-carboxamide;

5,6-dihydro-3,7-phenanthrolin-8(7H)-one-9-carboxamidine;

5,6-dihydro-2,7-phenanthrolin-8(7H)-one-9-(N,N-dimethyl)carboxamide;

4,5,6,7-tetrahydro-3H-benzo[3,4]cyclohepta[1,2-b]pyridin-3-one-2-thiocarboxamide;

5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:4,3-b']dipyridin-9-one-10-(N,N-diethyl)carboxamide;

5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:4,3-c']dipyridin-9-one-10-carboxamide;

5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:4,3-c']dipyridin-9-one-10-carboxamidine;

5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:3,4-b']dipyridin-9-one-10-carboxamidine; and

5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:3,4-c']dipyridin-9-one-10-thiocarboxamide.

EXAMPLE 9 Preparation of 2-Amino-5,6-dihydrobenzo[f]quinolin-3(4H)-one

Add 3.65 g of 5,6-dihydrobenzo[f]quinolin-3(4H)-one, to a solution of 4.2 g of sodium hydroxide in 65 ml of water containing 1.05 ml of bromine at 0°-5° C. Stir the resulting mixture at 100° for 3 hours. Cool and acidify the reaction mixture with concentrated hydrochloric acid. Stir this solution for 45 minutes and then cool this solution to give a precipitate. Filter the mixture and recrystallize the solid (methanol) to give the title compound.

EXAMPLE 10 Preparation of 2-(N-acetylamino)-5,6-dihydrobenzo[f]quinolin-3(4H)-one

To 2.0 gm of 2-amino-5,6-dihydrobenzo[f]quinolin-3(4H)-one, in 100 ml of chloroform containing 1 ml of pyridine add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.

Similarly, the following compounds of this invention may be prepared by using the above procedures and employing the appropriate starting materials:

3-amino-6-chloro-1,9-dihydro-2H-cyclopenta[1,2-b:4,3-b']dipyridin-2-one;

3amino-1,9-dihydro-2H-indeno-[2,1-b]pyridin-2-one;

3-amino-1,9-dihydro-2H-cyclopenta[1,2-b:4,3-c']dipyridin-2-one;

3-(N-acetylamino)-1,9-dihydro-2H-cyclopenta[1,2-b:3,4-c']dipyridin-2-one;

3-amino-1,9-dihydro-2H-cyclopenta[1,3-b:3,4-b']dipyridin-2-one;

2-aminobenzo[f]quinolin-3(4H)-one;

2-amino-8-chlorobenzo[f]quinolin-3(4H)-one;

2-(N-acetyl-N-methylamino)-5,6-dihydrobenzo[f]quinolin-3(4H)-one;

2-(N-acetylamino)benzo[f]quinolin-3(4H)-one;

2-amino-8-chloro-5,6-dihydrobenzo[f]quinolin-3(4H)-one;

9-amino-2-chloro-1,7-phenanthrolin-8(7H)-one;

9-amino-3,7-phenanthrolin-8(7H)-one;

9-amino-5,6-dihydro-3,7-phenanthrolin-8(7H)-one;

9-(N-acetylamino)-5,6-dihydro-3,7-phenanthiolin-8(7H)-one;

2-amino-4,5,6,7-tetrahydro-3H-benzo[3,4]cyclohepta[1,2-b]pyridin-3-one;

5,6,7,8-tetrahydro-10-amino-9H-cyclohepta[1,2-b:4,3-c']dipyridin-9-one;

EXAMPLE 11 Preparation of 5,6-Dihydrobenzo[f]quinolin-3(4H)-one

To a mixture of 60 ml of concentrated sulfuric acid and 15 ml of water, add 22.2 gm of 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one. Heat the system at reflux for 24 hours. Cool the system and pour the solution into 1 liter of ice/water. Neutralize the solution with 10N NaOH solution. Extract the solution with 300 ml of chloroform and dry the organic solution over anhydrous magnesium sulfate. Filter the solution and remove the solvent by stripping to give the title compound.

EXAMPLE 12 Preparation of 2-Chloro-5,6-dihydrobenzo[f]quinolin-3(4H)-one

Add 19.7 gm of 5,6-dihydrobenzo[f]quinolin-3(4H)-one to 300 ml of acetic acid. Bubble chlorine into the reaction solution for 4 hours at 100°. Cool the system and collect the product as a precipate. Dissolve the solid into water and neutralize the solution with 1N NaOH. Extract the product with chloroform. Dry the chloroform over anhydrous magnesium sulfate and filter the solution. Remove the solvent by stripping to give the title compound.

EXAMPLE 13 Preparation of 2-(N-Methylamino)-5,6-dihydrobenzo[f]quinolin-3(4H)-one

Add 23.1 gm of 2-chloro-5,6-dihydro-benzo[f]quinolin-3(4H)-one to 100 ml of 40% aqueous methylamine and 250 ml of water. Heat the system in a steel bomb at 140° C. for 5 days. Stop the reaction and isolate 2-(N-methylamino)-5,6-dihydro-benzo[f]quinolin-3(4H)-one.

EXAMPLE 14 Preparation of 2-Hydroxy-5,6-dihydrobenzo[f]quinolin-3(4H)-one

Add 23.1 gm of 2-chloro-5,6-dihydro-benzo[f]quinolin-3(4H)-one to 300 ml of methanol containing 30 gm of sodium methoxide. Heat the system in a steel bomb at about 200° C. for 12 hours. Stop the reaction, remove solvent, treat with water, and isolate the title compound.

Similarly, the following compounds of this invention may be prepared by using the above procedures and employing the appropriate starting materials;

10-chloro-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:4,3-C']dipyridin-9-one;

10-bromo-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:3,4-b']dipyridin-9-one;

10-chloro-5,6,7,8-tetrahydro-9H-cyclohepta[1,2-b:3,4-c']dipyridin-9-one;

2-hydroxybenzo[f]quinolin-3(4H)-one;

5,6-dihydro-2-hydroxybenzo[f]quinolin-3(4H)-one;

5,6,7,8-tetrahydro-10-(N,N-dimethylamino)-9H-cyclohepta[1,2-b:4,3-b']dipyridin-9-one;

5,6-dihydro-9-N-methylamino-3,7-phenathrolin-8(7H)-one;

5,6-dihydro-9-(N-ethylamino)-3,7-phenathrolin-8(7H)-one; and

5,6,7,8-tetrahydro-10-(N,N-di-n-propyl amino)-9H-cyclohepta[1,2-b:3,4-c']dipyridin-9-one.

The following formulations exemplify some of the dosage forms in which the compounds of this invention may be employed. In each, the active ingredient is designated by the term "Drug" which is meant to indicate the following compound:

2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one.

It is contemplated, however, that each of these exemplar compounds may be replaced by equally effective quantities of other compounds within the scope of formula I. All temperatures are in degrees Celsius.

EXAMPLE 15 Parenteral Dosage Forms

(a) Injection (Per vial)

    ______________________________________                                                        mg/vial                                                         ______________________________________                                         Drug Sterile Power                                                                              500                                                           ______________________________________                                    

Add sterile water for injection or bacteriostatic water for injection for reconstitution.

(b) Injectable Solution of drug

    ______________________________________                                         Ingredient              mg/ml                                                  ______________________________________                                         Drug                    20                                                     Methylparaben           0.2                                                    Propylparaben           1.6                                                    Sodium Bisulfite        3.2                                                    Disodium Edetate        0.1                                                    Water for Injection q.s. ad                                                                            1.0   ml                                               ______________________________________                                    

Method of Manufacture

1. Dissolve parabens in a portion (85% of the final volume) of the water for injection at 65°-70°.

2. Cool to 25°-35°. Charge and dissolve the sodium bisulfite and disodium edetate.

3. Charge and dissolve Drug.

4. Bring the solution to final volume by adding water for injection.

5. Filter the solution through 0.22 membrane and fill into appropriate containers.

6. Terminally sterilize the units by autoclaving. 

We claim:
 1. A compound of the formula ##STR10## wherein R is hydrogen or lower alkyl; R¹ is hydroxy, lower alkoxy, cyano,halogen, --NR² R³, --CONR² R³, --NHCOR², --COOR² (wherein R² and R³ are independently hydrogen, lower alkyl, or hydroxy lower alkyl) or ##STR11## wherein M is sulfur or NH; Z is selected from the group consisting of ##STR12## wherein n is 1,2,3 or 4; A is a substituted or unsubstituted benzo or pyrido ring which when substituted have 1 to 3 substituents independently selected from halogen, hydroxy, lower alkyl and lower alkoxy;or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1 wherein R¹ is hydroxy, lower alkoxy, cyano, --NR² R³, --CONR² R³, --NHCOR² wherein R² and R³ are independently hydrogen, lower alkyl or hydroxy lower alkyl.
 3. A compound of claim 2 wherein R¹ is cyano, amino or ##STR13##
 4. a compound of claim 1 wherein R is hydrogen or methyl.
 5. A compound of claim 1 wherein Z is ##STR14## wherein R, R¹, n, and A are as defined in claim
 1. 6. A compound of claim 5 wherein n is
 2. 7. A compound of claim 6 wherein R is hydrogen and R¹ is cyano.
 8. A compound of claim 7 wherein A is a benzo group; i.e., 2-cyano-5,6-dihydrobenzo[f]quinolin-3(4H)-one.
 9. A compound of claim 7 wherein A is a 3-pyrido group; i.e., 9-cyano-5,6-dihydro-3,7-phenanthrolin-8(7H)-one.
 10. A compound of claim 1 wherein Z is etheno wherein R, R¹ and A are as defined in claim
 1. 11. A compound of claim 10 wherein R is hydrogen and R¹ is cyano.
 12. A compound of claim 11 wherein A is a benzo group; i.e., 2-cyano-benzo[f]quinolin-3(4H)-one.
 13. A compound of claim 11 wherein A is a 3-pyrido group, i.e., 9-cyano-3,7-phenanthrolin-8(7H)-one.
 14. A method for increasing cardiac contractility in a patient requiring such treatment which comprises administering an amount effective in increasing cardiac contractility of a compound of the formula ##STR15## wherein R is hydrogen or lower alkyl; R¹ is hydrogen, hydroxy, lower alkoxy, cyano, lower alkyl, halogen, --NR² R³, --CONR² R³,--NHCOR², --COOR² (wherein R² and R³ are independently hydrogen, lower alkyl, or hydroxy lower alkyl) or ##STR16## wherein M is sulfur or NH; with the proviso that R and R¹ are not both hydrogen;Z is selected from the group consisting of ##STR17## wherein n is 1,2,3 or 4; A is a substituted or unsubstituted benzo or pyrido ring which when substituted have 1 to 3 substituents independently selected from halogen, hydroxy, lower alkyl and lower alkoxy;or a pharmaceutically acceptable salt thereof.
 15. A method for increasing cardiac contractility in a patient requiring such treatment which comprises administering an amount of the compound defined in claim 8 effective increasing cardiac contractility.
 16. The method of claim 14 wherein said compound is administered parenterally.
 17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount effective in increasing cardiac contractility of a compound defined in claim
 14. 18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount effective in increasing cardiac contractility of the compound defined in claim
 8. 19. The composition of claim 17 wherein said composition is adapted for parenteral administration. 